Aerosol formulations containing P134a and particulate medicaments

ABSTRACT

This invention relates to a pharmaceutical aerosol formulation containing a particulate medicament which is salmeterol or a physiologically acceptable salt or solvate thereof end 1,1,1,2-tetrafluoroethane as propellant, which formulation is free of surfactant or has less than 0.0001 % w/w surfactant based on the weight of medicament. The formulation may contain a further particulate medicament which is salbutamol, beclomethasone dipropionate or a physiologically acceptable salt or solvate thereof. A method of treating respiratory disorders which comprises administration by inhalation of an effective amount of the pharmaceutical aerosol formulation is also described.

The present application is a continuation of application Ser. No.08/328,959, filed Oct. 24, 1994 (now abandoned) which is a continuationof application Ser. No. 08/102,241, filed Aug. 5, 1993 (now abandoned),which is a divisional of application Ser. No. PCT/EP92/02808 filed Dec.4, 1992 (now abandoned).

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to aerosol formulations of use for theadministration of medicaments by inhalation.

2. Description of the Prior Art

The use of aerosols to administer medicaments has been known for severaldecades. Such aerosols generally comprise the medicament, one or morechlorofluorocarbon propellants and either a surfactant or a solvent,such as ethanol. The most commonly used aerosol propellants formedicaments have been propellant 11 (CCl₃ F) and/or propellant 114 (CF₂ClCF₂ Cl) with propellant 12 (CCl₂ F₂). However these propellants arenow believed to provoke the degradation of stratospheric ozone and thereis thus a need to provide aerosol formulations for medicaments whichemploy so called "ozone-friendly" propellants.

A class of propellants which are believed to have minimalozone-depleting effects in comparison to conventionalchlorofluorocarbons comprise fluorocarbons and hydrogen-containingchlorofluorocarbons, and a number of medicinal aerosol formulationsusing such propellant systems are disclosed in, for example, EP 0372777,WO91/04011, WO91/11173, WO91/11495 and WO91/14422. These applicationsare all concerned with the preparation of pressurised aerosols for theadministration of medicaments and seek to overcome the problemsassociated with the use of the new class of propellants, in particularthe problems of stability associated with the pharmaceuticalformulations prepared. The applications all propose the addition of oneor more of adjuvants such as alcohols, alkanes, dimethyl ether,surfactants (including fluorinated and non-fluorinated surfactants,carboxylic acids, polyethoxylates etc) and even conventionalchlorofluorocarbon propellants in small amounts intended to minimisepotential ozone damage.

Thus, for example EP 0372777 requires the use of1,1,1,2-tetrafluoroethane in combination with both a cosolvent havinggreater polarity than 1,1,1,2-tetrafluoroethane (e.g. an alcohol or alower alkane) and a surfactant in order to achieve a stable formulationof a medicament powder. In particular it is noted in the specificationat page 3, line 7 that "it has been found that the use of propellant134a (1,1,1,2-tetrafluoroethane) and drug as a binary mixture or incombination with a conventional surfactant such as sorbitan trioleatedoes not provide formulations having suitable properties for use withpressurised inhalers". Surfactants are generally recognised by thoseskilled in the art to be essential components of aerosol formulations,required not only to reduce aggregation of the medicament but also tolubricate the valve employed, thereby ensuring consistentreproducibility of valve actuation and accuracy of dose dispensed.Whilst WO91/11173, WO91/11495 and WO91/14422 are concerned withformulations comprising an admixture of drug and surfactant, WO91/04011discloses medicinal aerosol formulations in which the particulatemedicaments are pre-coated with surfactant prior to dispersal in1,1,1,2-tetrafluoroethane.

SUMMARY OF THE INVENTION

We have now surprisingly found that, in contradistinction to theseteachings, it is in fact possible to obtain satisfactory dispersions ofcertain medicaments in fluorocarbon or hydrogen-containingchlorofluorocarbon propellants such as 1,1,1,2-tetrafluoroethane withoutrecourse to the use of any surfactant or cosolvent in the composition,or the necessity to pre-treat the medicament prior to dispersal in thepropellant. More particularly, satisfactory dispersions may be formedwhere the medicament is selected from salmeterol, salbutamol,fluticasone propionate, beclomethasone dipropionate and physiologicallyacceptable salts and solvates thereof.

There is thus provided in one aspect of the invention a pharmaceuticalaerosol formulation which comprises particulate medicament selected fromthe group consisting of salmeterol, salbutamol, fluticasone propionate,beclomethasone dipropionate and physiologically acceptable salts andsolvates (for example hydrates) thereof and a fluorocarbon orhydrogen-containing chlorofluorocarbon propellant, which formulation issubstantially free of surfactant. By "substantially free of surfactant"is meant formulations which contain no significant amounts ofsurfactant, for example less than 0.0001% by weight of the medicament.

In an alternative embodiment the present invention provides apharmaceutical aerosol formulation as hereinbefore defined with theproviso that when said formulation consists essentially of salbutamoland 1,1,1,2-tetrafluoroethane in a weight ratio of 0.05:18, saidsalbutamol is present in the form of a physiologically acceptable salt.

The particle size of the particulate (e.g. micronised) medicament shouldbe such as to permit inhalation of substantially all of the medicamentinto the lungs upon administration of the aerosol formulation and willthus be less than 100 microns, desirably less than 20 microns, andpreferably in the range 1-10 microns, e.g. 1-5 microns.

Suitable pharmaceutically acceptable salts of the medicaments of use inthe formulations of the present invention include acid addition saltssuch as for example sulphates, hydrochlorides and xinafoates(1-hydroxy-2-naphthoate), amine salts or alkali metal salts (e.g.sodium). Salmeterol will preferably be in the form of its xinafoate saltand salbutamol will preferably be in the form of its sulphate salt.

The final aerosol formulation desirably contains 0.005-10% w/w,preferably 0.005-5% w/w, especially 0.01-1.0% w/w, of medicamentrelative to the total weight of the formulation.

The propellants for use in the invention may be any fluorocarbon orhydrogen-containing chlorofluorocarbon or mixtures thereof having asufficient vapour pressure to render them effective as propellants.Preferably the propellant will be a non-solvent for the medicament.Suitable propellants include, for example, C₁₋₄ hydrogen-containingchlorofluorocarbons such as CH₂ ClF, CClF₂ CHClF, CF₃ CHClF, CHF₂ CClF₂,CHClFCHF₂, CF₃ CH₂ Cl and CClF₂ CH₃ ; C₁₋₄ hydrogen-containingfluorocarbons such as CHF₂ CHF₂, CF₃ CH₂ F, CHF₂ CH₃ and CF₃ CHFCF₃ ;and perfluorocarbons such as CF₃ CF₃ and CF₃ CF₂ CF₃.

Where mixtures of the fluorocarbons or hydrogen-containingchlorofluorocarbons are employed they may be mixtures of the aboveidentified compounds or mixtures, preferably binary mixtures, with otherfluorocarbons or hydrogen-containing chlorofluorocarbons for exampleCHClF₂, CH₂ F₂ and CF₃ CH₃. Preferably a single fluorocarbon orhydrogen-containing chlorofluorocarbon is employed as the propellant.Particularly preferred as propellants are C₁₋₄ hydrogen-containingfluorocarbons such as 1,1,1,2-tetrafluoroethane(CF₃ CH₂ F) and1,1,1,2,3,3,3-heptafluoro-n-propane (CF₃ CHFCF₃).

It is desirable that the formulations of the invention contain nocomponents which may provoke the degradation of stratospheric ozone. Inparticular it is desirable that the formulations are substantially freeof chlorofluorocarbons such as CCl₃ F, CCl₂ F₂ and CF₃ CCl₃.

The propellant may additionally contain a volatile adjuvant such as asaturated hydrocarbon for example propane, n-butane, isobutane, pentaneand isopentane or a dialkyl ether for example dimethyl ether. Ingeneral, up to 50% w/w of the propellant may comprise a volatilehydrocarbon, for example 1 to 30% w/w. However, formulations which aresubstantially free of volatile adjuvants are preferred.

It is further desirable that the formulations of the invention aresubstantially free of liquid components of higher polarity than thepropellant employed. Polarity may be determined for example, by themethod described in European Patent Application Publication No. 0327777.In particular formulations which are substantially free of alcohols suchas ethanol are preferable. As used herein "substantially free" meansless than 1% w/w based upon the fluorocarbon or hydrogen-containingchlorofluorocarbon, in particular less than 0.5% for example 0.1% orless.

A particularly preferred embodiment of the invention provides apharmaceutical aerosol formulation consisting essentially of one or moreparticulate medicament selected from the group consisting of salmeterol,salbutamol, fluticasone propionate, beclomethasone dipropionate andphysiologically acceptable salts and solvates thereof, and one or morefluorocarbon or hydrogen-containing chlorofluorocarbon propellant.

It will be appreciated by those skilled in the art that the aerosolformulations according to the invention may, if desired, contain acombination of two or more active ingredients. Aerosol compositionscontaining two active ingredients (in a conventional propellant system)are known, for example, for the treatment of respiratory disorders suchas asthma. Accordingly the present invention further provides aerosolformulations in accordance with the invention which contain two or moreparticulate medicaments. Medicaments may be selected from suitablecombinations of the medicaments mentioned hereinbefore or may beselected from any other suitable drug useful in inhalation therapy andwhich may be presented in a form which is substantially completelyinsoluble in the selected propellant. Appropriate medicaments may thusbe selected from, for example, analgesics, e.g. codeine,dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations,e.g. diltiazem; antiallergics, e.g. cromoglycate, ketotifen ornedocromil; antiinfectives e.g. cephalosporins, penicillins,streptomycin, sulphonamides, tetracyclines and pentamidine;antihistamines, e.g. methapyrilene; anti-inflammatories, e.g.flunisolide, budesonide, tipredane or triamcinolone acetonide;antitussives, e.g. noscapine; bronchodilators, e.g. ephedrine,adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol,phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol,terbutaline, isoetharine, tulobuterol, orciprenaline, or(-)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]amino]methyl]benzenemethanol;diuretics, e.g. amiloride; anticholinergics e.g. ipratropium, atropineor oxitropium; hormones, e.g. cortisone, hydrocortisone or prednisolone;xanthines e.g. aminophylline, choline theophyllinate, lysinetheophyliinate or theophylline; and therapeutic proteins and peptides,e.g. insulin or glucagon. It will be clear to a person skilled in theart that, where appropriate, the medicaments may be used in the form ofsalts (e.g. as alkali metal or amine salts or as add addition salts) oras esters (e.g. lower alkyl esters) or as solvates (e.g. hydrates) tooptimise the activity and/or stability of the medicament and/or tominimise the solubility of the medicament in the propellant.

Particularly preferred aerosol formulations contain salbutamol (e.g. asthe free base or the sulphate salt) or salmeterol (e.g. as the xinafoatesalt) in combination with an antiinflammatory steroid such as abeclomethasone ester (e.g. the diproprionate) or a fluticasone ester(e.g. the propionate) or an antiallergic such as cromoglycate (e.g. thesodium salts. Combinations of salmeterol and fluticasone propionate orbeclomethasone. dipropionate, or salbutamol and fluticasone propionateor beclomethasone dipropionate are preferred, especially salmeterolxinafoate and fluticasone propionate or salbutamol and beclomethasonedipropionate.

The formulations of the invention may be prepared by dispersal of themedicament in the selected propellant in an appropriate container, e.g.with the aid of sonication. The process is desirably carried out underanhydrous conditions to obviate any adverse effects of moisture onsuspension stability.

The formulations according to the invention form weakly flocculatedsuspensions on standing but, surprisingly, these suspensions have beenfound to be easily redispersed by mild agitation to provide suspensionswith excellent delivery characteristics suitable for use in pressurisedinhalers, even after prolonged storage. Minimising and preferablyavoiding the use of formulation excipients e.g. surfactants, cosolventsetc in the aerosol formulations according to the invention is alsoadvantageous since the formulations may be substantially taste and odourfree, less irritant and less toxic than conventional. formulations.

The chemical and physical stability and the pharmaceutical acceptabilityof the aerosol formulations according to the invention may be determinedby techniques well known to those skilled in the art. Thus, for example,the chemical stability of the components may be determined by HPLCassay, for example, after prolonged storage of the product. Physicalstability data may be gained from other conventional analyticaltechniques such as, for example, by leak testing, by valve deliveryassay (average shot weights per actuation), by dose reproducibilityassay (active ingredient per actuation) and spray distribution analysis.

The particle size distribution of the aerosol formulations according tothe invention is particularly impressive and may be measured byconventional techniques, for example by cascade impaction or by the"Twin Impinger" analytical process. As used herein reference to the"Twin Impinger" assay means "Determination of the deposition of theemitted dose in pressurised inhalations using apparatus A" as defined inBritish Pharmacopaeia 1988, pages A204-207, Appendix XVII C. Suchtechniques enable the "respirable fraction" of the aerosol formulationsto be calculated. As used herein reference to "respirable fraction"means the amount of active ingredient collected in the lower impingementchamber per actuation expressed as a percentage of the total amount ofactive ingredient delivered per actuation using the twin impinger methoddescribed above. The formulations according to the invention have beenfound to have a respirable fraction of 20% or more by weight of themedicament, preferably 25 to 70%, for example 30 to 60%.

Optionally, the medicament may be surface-modified prior to itsdispersion in the propellant by treatment with a substantially non-polarliquid medium which is a non-solvent for the medicament. There is thusprovided in a further aspect of the invention an aerosol formulationcomprising particulate, surface-modified medicament, as defined herein,and a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant,which formulation is substantially free of surfactant. By"surface-modified medicament" is meant particles of medicament selectedfrom the group consisting of salmeterol, salbutamol, fluticasonepropionate, beclomethasone dipropionate and physiologically acceptablesalts and solvates thereof which have been surface-modified by admixturewith a substantially non-polar non-solvent liquid, followed by removalof the liquid. The substantially non-polar non-solvent liquid medium isconveniently an aliphatic hydrocarbon, e.g. a lower alkane, which issufficiently volatile to permit its ready evaporation, e.g. at ambienttemperature and pressure, after slurrying with medicament. The use ofisopentane as liquid medium is particularly advantageous in thisrespect.

The medicament is desirably slurried with the liquid medium underanhydrous conditions to obviate any adverse effects of moisture onsuspension stability. The slurry may advantageously be sonicated tomaximise the surface-modifying effect of the treatment. The liquid maybe removed by any convenient means for example by evaporation or byfiltration followed by evaporation, provided that following treatmentthe medicament is substantially free of the liquid. The formulations ofthe invention will be substantially free of the non-solvent non-polarliquid. Surface-modified medicament prepared by the above-describedprocess comprises a further aspect of the present invention.

The formulations according to the invention may be filled into canisterssuitable for delivering pharmaceutical aerosol formulations. Canistersgenerally comprise a container capable of withstanding the vapourpressure of the propellant used such as a plastic or plastic-coatedglass bottle or preferably a metal can, for example an aluminium canwhich may optionally be anodised, lacquer-coated and/or plastic-coated,which container is closed with a metering valve. The metering valves aredesigned to deliver a metered amount of the formulation per actuationand incorporate a gasket to prevent leakage of propellant through thevalve. The gasket may comprise any suitable elastomeric material such asfor example low density polyethylene, chlorobutyl, black and whitebutadiene-acrylonitrile rubbers, butyl rubber and neoprene. Suitablevalves are commercially available from manufacturers well known in theaerosol industry, for example, from Valois, France (e.g. DF10, DF30,DF60), Bespak plc, UK (e.g. BK300, BK356) and 3M-Neotechnic Ltd, UK(e.g. Spraymiser™).

Conventional bulk manufacturing methods and machinery well known tothose skilled in the art of pharmaceutical aerosol manufacture may beemployed for the preparation of large scale batches for the commercialproduction of filled canisters. Thus, for example, in one bulkmanufacturing method a metering valve is crimped onto an aluminium canto form an empty canister. The particulate medicament is added to acharge vessel and liquified propellant is pressure filled through thecharge vessel into a manufacturing vessel. The drug suspension is mixedbefore recirculation to a filling machine and an aliquot of the drugsuspension is then filled through the metering valve into the canister.Typically, in batches prepared for pharmaceutical use, each filledcanister is check-weighed, coded with a batch number and packed into atray for storage before release testing.

Each filled canister is conveniently fitted into a suitable channellingdevice prior to use to form a metered dose inhaler for administration ofthe medicament into the lungs or nasal cavity of a patient. Suitablechannelling devices comprise for example a valve actuator and acylindrical or cone-like passage through which medicament may bedelivered from the filled canister via the metering valve to the nose ormouth of a patient e.g. a mouthpiece actuator. Metered dose inhalers aredesigned to deliver a fixed unit dosage of medicament per actuation or"puff", for example in the range of 10 to 5000 microgram medicament perpuff.

Administration of medicament may be indicated for the treatment of mild,moderate or severe acute or chronic symptoms or for prophylactictreatment. It will be appreciated that the precise dose administeredwill depend on the age and condition of the patient, the particularparticulate medicament used and the frequency of administration and willultimately be at the discretion of the attendant physician. Whencombinations of medicaments are employed the dose of each component ofthe combination will in general be that employed for each component whenused alone. Typically, administration may be one or more times, forexample from 1 to 8 times per day, giving for example 1,2,3 or 4 puffseach time.

Suitable daily doses, may be, for example in the range 50 to 200microgram of salmeterol, 100 to 1000 microgram of salbutamol, 50 to 2000microgram of fluticasone propionate or 100 to 2000 microgram ofbeclomethasone dipropionate, depending on the severity of the disease.

Thus, for example, each valve actuation may deliver 25 microgramsalmeterol, 100 microgram salbutamol, 25, 50, 125 or 250 microgramfluticasone propionate or 50, 100, 200 or 250 microgram beclomethasonedipropionate. Typically each filled canister for use in a metered doseinhaler contains 100, 160 or 240 metered doses or puffs of medicament.

The filled canisters and metered dose inhalers described herein comprisefurther aspects of the present invention.

A still further aspect of the present invention comprises a method oftreating respiratory disorders such as, for example, asthma, whichcomprises administration by inhalation of an effective amount of aformulation as herein described.

The following non-limitative Examples serve to illustrate the invention.

EXAMPLE 1

Mioronised salmeterol xinafoate (24 mg) was weighed into a clean, dry,plastic-coated glass bottle and 1,1,1,2-tetrafluoroethane (18.2 g) wasadded from a vacuum flask. The bottle was quickly sealed with a blankaluminium ferrule. The resulting aerosol contained 0.132% w/w salmeterolxinafoate.

EXAMPLE 2

Micronised salmeterol xinafoate (38.28 g) and 1,1,1,2-tetrafluoroethane(36.36 kg) were added to a pressure vessel and mixed with a high shearmixer for 20 minutes. Aliquots (18.2 g) of the suspension were filledinto aluminium cans closed with a metering valve, filling under pressurethrough the valve using conventional filling equipment. The resultinginhalers contained 9.57 mg salmeterol xinafoate and delivered 25microgram salmeterol (39.9 microgram salt) per actuation.

EXAMPLE 3

Micronised fluticasone propionate (24 mg) was weighed into a clean, dry,plastic-coated glass bottle and 1,1,1,2-tetrafluoroethane (18.2 g) wasadded from a vacuum flask. The bottle was quickly sealed with a blankaluminium ferrule. The resulting aerosol contained 0.132% w/wfluticasone propionate.

EXAMPLES 4 AND 5

Micronised fluticasone propionate (66 mg or 6.6 mg) was weighed directlyinto each of 100 open aluminium cans and a metering valve was thencrimped into place on each can. 1,1,1,2-Tetrafluoroethane (18.2 g) wasthen added to each canister under pressure, through the valve, and eachfilled canister shaken to disperse the drug. The resulting inhalerscontained 66 or 6.6 mg fluticasone propionate and delivered 250 or 25microgram fluticasone propionate per actuation (Examples 4 and 5respectively).

EXAMPLE 6

Micronised salbutamol (24 mg) was weighed into a clean, dry,plastic-coated glass bottle and 1,1,1,2-tetrafluoroethane (18.2 g) wasadded from a vacuum flask. The bottle was quickly sealed with a blankaluminium ferrule. The resulting aerosol contained 0.132% w/wsalbutamol.

EXAMPLES 7 AND 8

Micronised salbutamol (24 mg or 48 mg) was weighed directly into each of3 open aluminium cans. 1,1,1,2-Tetrafluoroethane (18.2 g) was added toeach can from a vacuum flask and a metering valve was then crimped intoplace. Each filled canister was then shaken in an ultrasonic bath for 8minutes. The resulting inhalers contained 24 mg or 48 mg salbutamol anddelivered 100 or 200 microgram salbutamol per actuation (Examples 7 and8 respectively).

EXAMPLE 9

Micronised salbutamol sulphate (31.7 mg) was weighed into a clean, dry,plastic-coated glass bottle and 1,1,1,2-tetrafluoroethane (18.2 g) wasadded from a vacuum flask. The bottle was quickly sealed with a blankaluminium ferrule. The resulting aerosol contained 0.174% w/w salbutamolsulphate.

EXAMPLE 10

Micronised salbutamol sulphate (31.7 mg) was weighed directly into eachof 4 open aluminium cans. 1,1,1,2-Tetrafluoroethane (18.2 g) was addedto each can from a vacuum flask and a metering valve was then crimpedinto place. Each filled canister was then shaken in an ultrasonic bathfor 5 minutes. The resulting inhalers contained 31.7 mg salbutamolsulphate and delivered 100 microgram salbutamol per actuation.

EXAMPLE 11

Isopentane (25 ml) was added to micronised salmeterol xinafoate (0.5 g)to form a slurry, which was sonicated for 3 minutes. The resultingsuspension was dried by evaporating the isopentane at ambienttemperature to yield surface-modified salmeterol xinafoate. Samples ofthis product (11.6 mg) were weighed into aluminium aerosol cans and1,1,1,2-tetrafluoroethane (18.2 g-99.95% w/w of total fill weight) wasadded to each can, whereafter suitable metering valves were crimped ontothe cans, which were then each sonicated for 5 minutes. The resultingaerosols contained salmeterol in an amount equivalent to 240 actuationsat 25 microgram per actuation.

EXAMPLE 12

Micronised beclomethasone dipropionate monohydrate (68 mg) was weighedinto a clean, dry, plastic-coated glass bottle and1,1,1,2-tetrafluoroethane (to 18.2 g) was added from a vacuum flask. Thebottle was quickly sealed with a metering valve. The resulting aerosoldispensed 250 microgram beclomethasone dipropionate (as the monohydrate)per 75.8 mg actuation.

EXAMPLE 13

Micronised salmeterol xinafoate (9.57 mg) is weighed directly into analuminium can and 1,1,1,2,3,3,3-heptafluoro-n-propane (to 21.4 g) addedfrom a vacuum flask. A metering valve is crimped into place and thefilled canister sonicated for five minutes. The aerosol delivers 25microgram salmeterol per actuation.

EXAMPLE 14

Micronised fluticasone propionate (13.3 mg) is weighed directly into analuminium can and 1,1,1,2,3,3,3-heptafluoro-n-propane (to 21.4 g) addedfrom a vacuum flask. A metering valve is crimped into place and thefilled canister sonicated for five minutes. The aerosol delivers 50microgram fluticasone propionate per actuation.

EXAMPLE 15

Micronised salbutamol sulphate (29 mg) was weighed directly into analuminium can and 1,1,1,2,3,3,3-heptafluoro-n-propane (to 21.4 g) addedfrom a vacuum flask. A metering valve was crimped into place and thefilled canister sonicated for five minutes. The aerosol delivered 100microgram salbutamol per actuation.

EXAMPLE 16

Micronised beclomethasone diproprionate monohydrate (62 mg) was weigheddirectly into an aluminium can and 1,1,1,2,3,3,3-heptafluoro-n-propane(to 21.4 g) added from a vacuum flask. A metering valve was crimped intoplace and the filled canister sonicated for five minutes. The aerosoldelivered 250 microgram beclomethasone diproprionate per actuation.

EXAMPLE 17

    ______________________________________                                                       Per Inhaler % w/w                                                                           Per Actuation                                    ______________________________________                                        Salmeterol xinafoate                                                                         0.048         36.25 microgram                                  Fluticasone propionate                                                                       0.066         50 microgram                                     1,1,1,2-Tetrafluoroethane                                                                    to 100        to 75.8 mg                                       ______________________________________                                    

Micronised medicaments were weighed into an aluminium can,1,1,1,2-tetrafluoroethane (18.2 g) was added from a vacuum flask and ametering valve was crimped into place.

EXAMPLE 18

    ______________________________________                                                       Per Inhaler % w/w                                                                           Per Actuation                                    ______________________________________                                        Salmeterol xinafoate                                                                         0.048         36.25 microgtam                                  Fluticasone propionate                                                                       0.165         125 microgram                                    1,1,1,2-Tetrafluoroethane                                                                    to 100        to 75.8 mg                                       ______________________________________                                    

Micronised medicaments were weighed into an aluminium can,1,1,1,2-tetrafluoroethane (18.2 g) was added from a vacuum flask and ametering valve was crimped into place.

EXAMPLE 19

    ______________________________________                                                       Per Inhaler % w/w                                                                           Per Actuation                                    ______________________________________                                        Salmeterol xinafoate                                                                         0.048         36.25 microgram                                  Fluticasone propionate                                                                       0.132         100 microgram                                    1,1,1,2-Tetrafluoroethane                                                                    to 100        to 75.8 mg                                       ______________________________________                                    

EXAMPLE 20

    ______________________________________                                                       Per Inhaler % w/w                                                                           Per Actuation                                    ______________________________________                                        Salmeterol xinafoate                                                                         0.048         36.25 microgram                                  Fluticasone propionate                                                                       0.330         250 microgram                                    1,1,1,2-Tetrafluoroethane                                                                    to 100        to 75.8 mg                                       ______________________________________                                    

EXAMPLE 21

    ______________________________________                                                       Per Inhaler % w/w                                                                           Per Actuation                                    ______________________________________                                        Salbutamol*    0.132         100 microgram                                    Fluticasone propionate                                                                       0.132         100 microgram                                    1,1,1,2-Tetrafluoroethane                                                                    to 100        to 75.8 mg                                       ______________________________________                                         *as free base or an equivalent weight of salt e.g. sulphate              

EXAMPLE 22

    ______________________________________                                                       Per Inhaler % w/w                                                                           Per Actuation                                    ______________________________________                                        Salbutamol*    0.264         200 microgram                                    Fluticasone propionate                                                                       0.330         250 microgram                                    1,1,1,2-Tetrafluoroethane                                                                    to 100        to 75.8 mg                                       ______________________________________                                         *as free base or an equivalent weight of salt e.g. sulphate              

EXAMPLE 23

    ______________________________________                                                        Per Inhaler % w/w                                                                           Per Actuation                                   ______________________________________                                        Salmeterol xinafoate                                                                          0.048         36.25 microgram                                 Beclomethasone dipropionate                                                                   0.066         50 microgram                                    1,1,1,2-Tetrafluoroethane                                                                     to 100        to 75.8 mg                                      ______________________________________                                    

EXAMPLE 24

    ______________________________________                                                       Per Inhaler % w/w                                                                           Per Actuation                                    ______________________________________                                        Salmeterol xinafoate                                                                         0.048         36.25 microgram                                  Fluticasone propionate                                                                       0.264         200 microgram                                    1,1,1,2-Tetrafluoroethane                                                                    to 100        to 75.8 mg                                       ______________________________________                                    

EXAMPLE 25

    ______________________________________                                                        Per Inhaler % w/w                                                                           Per Actuation                                   ______________________________________                                        Salbutamol*     0.132         100 microgram                                   Beclomethasone dipropionate                                                                   0.066         50 microgram                                    1,1,1,2-Tetrafluoroethane                                                                     to 100        to 75.8 mg                                      ______________________________________                                         *as free base or an equivalent weight of salt e.g. sulphate              

EXAMPLE 26

    ______________________________________                                                        Per Inhaler % w/w                                                                           Per Actuation                                   ______________________________________                                        Salbutamol*     0.264         200 microgram                                   Beclomethasone dipropionate                                                                   .0.264        200 microgram                                   1,1,1,2-Tetrafluoroethane                                                                     to 100        to 75.8 mg                                      ______________________________________                                         *as free base or an equivalent weight of salt e.g. sulphate              

In Examples 19 to 26 micronised medicaments are weighed into aluminiumcans, 1,1,1,2-tetrafluoroethane (18.2 g) is added from a vacuum flask,and metering valves are crimped into place.

We claim:
 1. A pharmaceutical aerosol formulation consisting essentiallyof a particulate medicament which is salmeterol or a physiologicallyacceptable salt or solvate thereof and 1,1,1,2-tetrafluoroethane aspropellant, which formulation contains less than 0.0001% w/w surfactantbased upon the weight of medicament, the particulate medicament beingpresent in an amount of from 0.005 to 5% w/w relative to the totalweight of the formulation and having a particle size of less than 100microns.
 2. A formulation as claimed in claim 1 wherein the particulatemedicament is present in an amount of 0.01 to 1% w/w relative to thetotal weight of the formulation.
 3. A formulation as claimed in claim 1which has a respirable fraction of 20% or more by weight of particulatemedicament.
 4. A formulation as claimed in claim 1 wherein thesalmeterol is in the form of its xinafoate salt.
 5. A pharmaceuticalaerosol formulation consisting essentially of a particulate medicamentwhich is salmeterol or a physiologically acceptable salt or solvatethereof and 1,1,1,2-tetrafluoroethane as propellent, the particulatemedicament being present in an amount of from 0.005 to 5% w/w relativeto the total weight of the formulation and having a particle size ofless than 100 microns, which formulation is free of surfactant.
 6. Apharmaceutical aerosol formulation consisting of particulate medicamentwhich is salmeterol or a physiologically acceptable salt or solvatethereof and 1,1,1,2-tetrafluoroethane as propellant, the particulatemedicament being present in an amount of from 0.005 to 5% w/w relativeto the total weight of the formulation and having a particle size ofless than 100 microns.
 7. A formulation as claimed in claim 5 whereinthe particulate medicament is present in an amount of 0.01 to 1% w/wrelative to the total weight of the formulation.
 8. A formulation asclaimed in claim 6 wherein the particulate medicament is present in anamount of 0.01 to 1% w/w relative to the total weight of theformulation.
 9. A formulation as claimed in claim 5 wherein thesalmeterol is in the form of its xinafoate salt.
 10. A formulation asclaimed in claim 6 wherein the salmeterol is in the form of itsxinafoate salt.
 11. A formulation as claimed in claim 5 which has arespirable fraction of 20% or more by weight of particulate medicament.12. A formulation as claimed in claim 6 which has a respirable fractionof 20% or more by weight of particulate medicament.
 13. A pharmaceuticalaerosol formulation consisting essentially of particulate medicamentwhich is salmeterol or a physiologically acceptable salt or solvatethereof, a particulate medicament selected from the group consisting ofsalbutamol, beclomethasone dipropionate and physiologically acceptablesalts and solvates thereof, and 1,1,1,2-tetrafluoroethane as propellant,which formulation contains less than 0.0001% w/w surfactant based uponthe weight of medicament, the particulate medicaments being present inan amount of from 0.005 to 5% w/w relative to the total weight of theformulation and having a particle size of less than 100 microns.
 14. Apharmaceutical aerosol formulation consisting of particulate medicamentconsisting of salmeterol or a physiologically acceptable salt or solvatethereof, a particulate medicament selected from the group consisting ofsalbutamol, beclomethasone dipropionate and physiologically acceptablesalts and solvates thereof, and 1,1,1,2-tetrafluoroethane as propellant,the particulate medicaments being present in an amount of from 0.005 to5% w/w relative to the total weight of the formulation and having aparticle size of less than 100 microns.
 15. A formulation as claimed inclaim 13 wherein the particulate medicaments are present in an amount of0.01 to 1% w/w relative to the total weight of the formulation.
 16. Aformulation as claimed in claim 14 wherein the particulate medicamentsare present in an amount of 0.01 to 1% w/w relative to the total weightof the formulation.
 17. A formulation as claimed in claim 13 wherein thesalmeterol is in the form of its xinafoate salt.
 18. A formulation asclaimed in claim 13 wherein the salmeterol is in the form of itsxinafoate salt.
 19. A formulation as claimed in claim 13 which has arespirable fraction of 20% or more by weight of the particulatemedicaments.
 20. A formulation as claimed in claim 14 which has arespirable fraction of 20% or more by weight of the particulatemedicaments.
 21. A formulation as claimed in claim 13 which formulationis free of surfactant.
 22. A method of treating respiratory disorderswhich comprises administration by inhalation of an effective amount ofthe pharmaceutical aerosol formulation of claim
 1. 23. A method asclaimed in claim 22 wherein the particulate medicament is present in anamount of 0.01 to 1% w/w relative to the total weight of theformulation.
 24. A method as claimed in claim 22 wherein the salmeterolis in the form of its xinafoate salt.
 25. A method as claimed in claim22 which has a respirable fraction of 20% or more by weight ofparticulate medicament.
 26. A method of treating respiratory disorderswhich comprises administration by inhalation of an effective amount ofthe pharmaceutical aerosol formulation of claim
 5. 27. A method asclaimed in claim 26 wherein the salmeterol is in the form of itsxinafoate salt.
 28. A method as claimed in claim 26 wherein theparticulate medicament is present in an amount of 0.01 to 1% w/wrelative to the total weight of the formulation.
 29. A method oftreating respiratory disorders which comprises administration byinhalation of an effective amount of the pharmaceutical aerosolformulation of claim
 6. 30. A method as claimed in claim 29 wherein theparticulate medicament is present in an amount of 0.01 to 1% w/wrelative to the total weight of the formulation.
 31. A method as claimedin claim 29 wherein the salmeterol is in the form of its xinafoate salt.32. A method as claimed in claim 29 which has a respirable fraction of20% or more by weight of particulate medicament.
 33. A method oftreating respiratory disorders which comprises administration byinhalation of the pharmaceutical aerosol formulation of claim
 13. 34. Amethod as claimed in claim 33 wherein the particulate medicaments arepresent in an amount of 0.01 to 1% w/w relative to the total weight ofthe formulation.
 35. A method as claimed in claim 33 wherein thesalmeterol is in the form of its xinafoate salt.
 36. A method as claimedin claim 33 which has a respirable fraction of 20% or more by weight ofthe particulate medicaments.
 37. A method of treating respiratorydisorders which comprises administration by inhalation of thepharmaceutical aerosol formulation of claim
 14. 38. A method as claimedin claim 37 wherein particulate medicaments are present in an amount of0.01 to 1% w/w relative to the total weight of the formulation.
 39. Amethod as claimed in claim 37 wherein the salmeterol is in the form ofits xinafoate salt.